Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum.
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are autosomal dominant osteochondrodysplasias that result in mild to severe short-limb dwarfism and early-onset osteoarthrosis. PSACH and some forms of MED result from mutations in the gene for cartilage oligomeric matrix protein (COMP; OMIM 600310 [http://www3.ncbi.nlm. nih.gov:80/htbin-post/Omim/dispmim?600310]). We report the identification of COMP mutations in an additional 14 families with PSACH or MED phenotypes. Mutations predicted to result in single-amino acid deletions or substitutions, all in the region of the COMP gene encoding the calmodulin-like repeat elements, were identified in patients with moderate to severe PSACH. We also identified within this domain a missense mutation that produced MED Fairbank. In two families, one with mild PSACH and the second with a form of MED, we identified different substitutions for a residue in the carboxyl-terminal globular region of COMP. Both the clinical presentations of these two families and the identification of COMP-gene mutations provide evidence of phenotypic overlap between PSACH and MED. These data also reveal a role for the carboxyl-terminal domain in the structure and/or function of COMP.
Briggs
M D
MD
Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Cedars-Sinai Research Institute, Los Angeles, CA, USA.
Mortier
G R
GR
Cole
W G
WG
King
L M
LM
Golik
S S
SS
Bonaventure
J
J
Nuytinck
L
L
De Paepe
A
A
Leroy
J G
JG
Biesecker
L
L
Lipson
M
M
Wilcox
W R
WR
Lachman
R S
RS
Rimoin
D L
DL
Knowlton
R G
RG
Cohn
D H
DH
D000130:Achondroplasia / Q000145:classification / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002356:Cartilage; D064236:Cartilage Oligomeric Matrix Protein; D002648:Child; D003062:Codon; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D005260:Female; D005799:Genes, Dominant; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D064235:Matrilin Proteins; D010009:Osteochondrodysplasias / Q000145:classification / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational
D064236:Cartilage Oligomeric Matrix Protein; D003062:Codon; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human